1. Field of the Invention
The invention relates to a method of identifying and treating patients at risk or in early onset of diabetes mellitus by first determining gastric emptying patterns and then treating with an appropriate drug. Treatment comprises administration of a pharmaceutical preparation having the ability to inhibit or block gastric emptying. In particular, drugs that affect gut motility are useful as a method of treatment in reducing gastric emptying rates to a near normal range, effectively slowing delivery of glucose to the duodenum and reducing hyperglycemia.
2. Description of Related Art
In recent years the role of the stomach in glucose homeostasis has become recognized (1). In 1982, Thompson described gastric emptying as an important determinant of the oral glucose tolerance test and suggested that the glucose tolerance test could be used to assess gastric emptying. In 1983 Brener et aI. (2) described characteristic gastric emptying of glucose solutions in normal human subjects In their studies they discovered that glucose empties from the stomach in a constant and linear fashion at an average of 2.13 kcal/min regardless of the concentration of the glucose solution Prior to this study, it was widely believed that all liquids emptied in an exponential manner. It is Brener's hypothesis that a dynamic "closed loop" feedback interrelationship exists between the stomach and the duodenum to control the delivery of calories from the stomach.
Keshavarzian et aI. (3) have studied gastric emptying in a heterogeneous group of diabetics with insulin-dependent diabetes mellitus and non-insulin dependent diabetes mellitus who had been diagnosed for more than 5 years. Although Keshavarzian emphasized the delay in gastric emptying, particularly with solids, some diabetic subjects in the study exhibited a more rapid gastric emptying compared to controls. Liquid gastric emptying was generally the same for both the controls and diabetics with the gastric half-emptying time (t1/2) showing no significant difference. It was noted that some of the patients exhibited abnormally fast emptying, but no significance was associated with the observation.
Campbell et aI. (4) described delayed gastric emptying in 10 of 12 diabetic subjects. Although the majority of the patients showed delayed gastric emptying, two of the subjects exhibited more rapid gastric emptying rates compared with controls.
Horowitz et aI. (5) described delayed gastric and esophageal emptying in 20 subjects with non-insulin dependent diabetes mellitus. The duration of known diabetes in the subjects ranged from 1-20 years. Although two of the subjects exhibited more rapid than normal liquid gastric emptying, the group of 20 as a whole exhibited delayed liquid gastric emptying (t1/2 slower than in normal patients, p&lt;0.05). There was significant delay of solid food emptying in these patients (increased retention of solid food at 100 min, p&lt;0.001).
Gastric emptying has been studied as a non-invasive diagnostic tool as an indicator of metabolic and neural disturbances. For example, chronic forms of gastric stasis can be caused by innervation abnormalities in diabetics with autonomic neuropathy (6). Many other conditions have been studied, including those in patients who had stomach operations or diseases of the gastrointestinal tract. Generally, the majority had delayed gastric emptying (7). In particular, delayed gastric emptying appears to be a phenomenon associated with diabetes. It has been recognized that by delaying nutrient absorption, glucose disposal and insulin economy may be enhanced (14).
Methods of regulating pyloric functions are known in the art. Diabetic gastroparesis and hypertrophic pyloric stenosis are examples of conditions successfully treated (8); delayed gastric emptying has been treated with drugs that accelerate the emptying process, for example metoclopramide or domperidone (11). An opposite effect is shown by Propantheline and opiates which delay gastric emptying (11).
There is some information on the effects of different compounds on enzyme components of pancreatic secretion, for example, the role of cholecystokinin (CCK) (12) and possible regulatory control by other gut hormones, such as VIP which stimulate insulin release from the pancreas (9). It is known that CCK has a significant role in regulating glucose homeostasis in humans (13) and that it delays gastric emptying and reduces hyperglycemia (14). However, the connection between CCK secretion on gastric emptying and insulin release in normal and diabetic patients has not yet been fully evaluated (10).
Studies so far reported indicate that in diabetic patients, delayed gastric emptying is typical. However, until now, there was no realization that certain classes of patients, those-not yet manifesting diabetes, those at risk to develop diabetes and those in early stages of diabetes or having non-insulin dependent diabetes, exhibit abnormally rapid gastric emptying. It was this unexpected and surprising discovery that led to the development of a method of a simple treatment By delaying gastric emptying in this group of patients at high risk to develop diabetes, insulin and plasma glucose levels may be maintained at levels much closer to normal levels. This is a first and significant step in early treatment of those at risk for developing debilitating forms of diabetes, even insulin-dependent diabetes, and may delay or forestall completely the usual progress of the disease.